Type 1 Diabetes TrialNet: Toronto Clinical Centre

描述（由申请人提供）：本申请的第一个目的是描述多伦多大学儿童医院TrialNet临床中心的优势和成功。多伦多临床中心通过其高能力的研究人员Diane Wherrett和Jeffrey Mahon博士为1型糖尿病发展的TrialNet自然史研究提供了高水平的招聘，提供糖尿病，临床试验和1型糖尿病免疫学方面的专业知识，其优秀的协调员，机构支持和资源，一个富有成效的加拿大附属网络和广泛的本地合作伙伴关系在多伦多地区。这项研究的招募在14个北美TrialNet临床中心中排名第4。该中心在TrialNet研究中发挥了领导作用：Mahon博士是1型糖尿病自然史研究的主席，Wherrett博士是重组人谷氨酸脱羧酶（rhGAD 65）在明矾（GAD-alum）中配制对新发受试者1型糖尿病进展的影响研究的主席。它为TrialNet的所有研究做出了积极贡献，以保护新近发病的糖尿病患者的胰岛素分泌。第二个目的是确定肠促胰岛素模拟物艾塞那肽（Byetta（））单独或与抗CD 20单克隆抗体利妥昔单抗（Rituxan（））联合治疗新发现的免疫介导的1型糖尿病患者的疗效和安全性。该提案的主要目的将是检验以下假设：与单独使用任何一种药物相比，艾塞那肽和rituxamab的组合更有效地保护内源性胰岛素分泌。主要结局将是研究入组后1年2小时混合餐葡萄糖耐量试验期间的刺激C肽曲线下面积（AUC）。本研究为安慰剂对照双盲研究。这项拟议研究的基本原理结合了利妥昔单抗的免疫调节作用，以减少β细胞自身免疫与艾塞那肽的β细胞再生潜力，以改善胰岛素分泌。已发现内源性胰岛素分泌保持与低血糖、肾病和视网膜病变的糖尿病并发症的发生率降低相关。 公共卫生相关性：寻找方法来保持1型糖尿病的胰岛素分泌是至关重要的，在预防疾病，并在降低那些受影响的严重程度。利妥昔单抗和艾塞那肽的组合具有减少胰岛素产生细胞的损失并促进其发育的潜力。这种疗法的成功可能会改善1型糖尿病患者的长期健康状况。

DESCRIPTION (provided by applicant): The first objective of this application is describe the strengths and successes of the TrialNet Clinical Center at the Hospital for Sick Children/University of Toronto. The Toronto Clinical Center has shown a high level of recruitment for the TrialNet Natural History of the Development of Type 1 Diabetes Study through its highly capable investigators, Drs. Diane Wherrett and Jeffrey Mahon, providing expertise in diabetes, clinical trials and immunology of type 1 diabetes, its excellent coordinators, institutional support and resources, a productive Canadian affiliate network and extensive local partnerships in the Toronto area. Recruitment to this study ranks 4th of the 14 North American TrialNet Clinical Centers. This center has provided leadership in TrialNet studies: Dr. Mahon, chair of the Natural History Study of the Development of Type 1 Diabetes Study and Dr. Wherrett, chair of the Effects of Recombinant Human Glutamic Acid Decarboxylase (rhGAD65) Formulated in Alum (GAD-alum) on the Progression of Type 1 Diabetes in New Onset Subjects Study. It has contributed actively to all of TrialNet's studies to preserve insulin secretion in recent onset diabetes. The second objective is to determine the efficacy and safety of the incretin mimetic exenatide (Byetta(), alone and in combination with the anti-CD20 monoclonal antibody rituximab (Rituxan(), in patients with newly recognized immune-mediated Type 1 Diabetes. The proposal's primary objective will be to test the hypothesis that the combination of exenatide and rituxamab more effectively preserves endogenous insulin secretion compared to either drug alone. The primary outcome will be the area under the stimulated C-peptide curve (AUC) during a 2 hour mixed meal glucose tolerance test one year after study entry. The study will be placebo controlled and double blinded. The rationale for this proposed study combines the immunomodulatory effect of rituximab to reduce beta cell autoimmunity with the beta cell regenerative potential of exenatide to improve insulin secretion. Preserved endogenous insulin secretion has been found to be associated with reduced of rates of the diabetes complications of hypoglycemia, nephropathy and retinopathy. PUBLIC HEALTH RELEVANCE: Finding methods to preserve insulin secretion in type 1 diabetes are crucial in preventing the disease and in reducing the severity in those affected. The combination of rituximab and exenatide has the potential to both reduce the loss of insulin-producing cells and to promote their development. Success of this therapy could result in the improvement of long term health for those with type 1 diabetes.